Since the discovery of insulin in the last century, there has been an effort to develop improved methods for the delivery of biomolecules such as proteins to patients via, e.g., pulmonary, nasal, subcutaneous, and oral routes. The main avenues of research in the field of biomolecule delivery include chemical modification of proteins with sugars, amino acids, or pegylation; or the encapsulation, entrapment, or incorporation of proteins within carriers. Nanotechnology has played a role in the design of optimal delivery carriers for biomolecules, with polymeric nanoparticles being effective platforms for, e.g., protein delivery due to the possibility of fine-tuning their biophysicochemical properties, in addition to their ability to protect and release proteins in a controlled manner. However, the clinical translation of protein drugs and protein-delivering nanomedicines has been hindered due to difficulties in the development and manufacturing of protein-based therapeutics that must be overcome to achieve clinical translation. Limitations such as synthetic chemical coupling and formulation parameters such as homogenization, sonication, extrusion, and exposure to solvents lead to the inactivation of biomolecules.